Newborn screening for severe combined immunodeficiency and T-cell lymphopenia in California: results of the first 2 years

Abstract

Background: Assay of T-cell receptor excision circles (TRECs) in dried blood spots obtained at birth permits population-based newborn screening (NBS) for severe combined immunodeficiency (SCID).

Objective: We sought to report the first 2 years of TREC NBS in California.

Methods: Since August 2010, California has conducted SCID NBS. A high-throughput TREC quantitative PCR assay with DNA isolated from routine dried blood spots was developed. Samples with initial low TREC numbers had repeat DNA isolation with quantitative PCR for TRECs and a genomic control, and immunophenotyping was performed within the screening program for infants with incomplete or abnormal results. Outcomes were tracked.

Results: Of 993,724 infants screened, 50 (1/19,900 [0.005%]) had significant T-cell lymphopenia. Fifteen (1/66,250) required hematopoietic cell or thymus transplantation or gene therapy; these infants had typical SCID (n = 11), leaky SCID or Omenn syndrome (n = 3), or complete DiGeorge syndrome (n = 1). Survival to date in this group is 93%. Other T-cell lymphopenic infants had variant SCID or combined immunodeficiency (n = 6), genetic syndromes associated with T-cell impairment (n = 12), secondary T-cell lymphopenia (n = 9), or preterm birth (n = 8). All T-cell lymphopenic infants avoided live vaccines and received appropriate interventions to prevent infections. TREC test specificity was excellent: only 0.08% of infants required a second test, and 0.016% required lymphocyte phenotyping by using flow cytometry.

Conclusions: TREC NBS in California has achieved early diagnosis of SCID and other conditions with T-cell lymphopenia, facilitating management and optimizing outcomes. Furthermore, NBS has revealed the incidence, causes, and follow-up of T-cell lymphopenia in a large diverse population.

Figure 1

A) California SCID NBS. Sample numbers are shown at each stage (boxes) according to TREC and β-Actin and nursery care as proxy for clinical status. [Also see Online Repository Fig. E1]. Infants with low TRECs on 2 DBS or positive initial results were recalled to receive flow cytometry. B) Distribution of regular nursery vs. neonatal intensive care unit (NICU) samples at each NBS stage. *14 infants deceased, 1 lost to follow-up before flow cytometry.

Figure 2

T cell lymphopenia (TCL) by intervention and underlying condition. Cases requiring immune restoring therapy included 11 typical and 3 leaky SCID and 1 complete DiGeorge syndrome. There were 6 variant SCID, 12 congenital syndromes, 9 secondary TCL, and 8 preterm infants (weight ranges shown). All were advised to avoid live rotavirus and other live vaccines and to receive only CMV negative, irradiated blood products.

Figure 3

T cell concentrations in infants with initial T cell lymphopenia associated with preterm birth, obtained at gestational ages on the X-axis. Birth weights are indicated. Subsequent T cell concentrations were >1,500 cells/μL, dotted line, the threshold set by California NBS program.